The impact of vector-mediated neutrophil recruitment on cutaneous leishmaniasis

Abstract

The dynamic process of pathogen transmission by the bite of an insect vector combines several biological processes that have undergone extensive co-evolution. Whereas the host response to an insect bite is only occasionally confronted with the parasitic pathogens that competent vectors might transmit, the transmitted parasites will always be confronted with the acute, wound-healing response that is initiated by the bite itself. Invariably, this response involves neutrophils. In the case of Leishmania, infection is initiated in the skin following the bite of an infected sand fly, suggesting that Leishmania must possess some means to survive their early encounter with recruited neutrophils at the bite site. Here, we review the literature regarding the impact of neutrophils on the outcome of infection with Leishmania, with special attention to the role of the sand fly bite.

Figure 1

Life cycle of L. major incorporating the influence of sand fly bite and the role of neutrophils in the pathogenesis of disease. (A) Phlebotomine spp. of sand flies take a blood meal from an infected individual, acquiring parasites in the process. Intracellular amastigotes undergo transformation, growth and differentiation in the sand fly midgut, eventually becoming metacyclic promastogites positioned in the anterior gut. The picture is of P. dubosqi infected with RFP-expressing L. major. (B) In search of a second blood meal, sand flies again probe the skin of a mammalian host, creating a hemorrhagic pool from which to feed while simultaneously depositing parasites into the dermis and epidermis. Tissue damage caused by sand fly probing induces highly localized neutrophil recruitment and the formation of neutrophil ‘plugs’ in the regions of skin punctured by the sand fly proboscis. The picture is of L.m.-RFP metacyclic promastigotes deposited among the Lys-GFP^hi neutrophils, and neutrophil plugs extending up through the epidermis and stratum corneum. (C) Neutrophils dominate in sites of tissue damage following sand fly probing and phagocytose the majority (80–90%) of parasites. Smaller numbers of parasites also gain direct access to macrophages/monocytes (10–20%). A few parasites may gain direct access to resident dermal dendritic cells (1–5%). (D) Infected neutrophils in the skin fail to kill L.m., and the parasitized cells acquire apoptotic markers such as phosphatidylserine (indicated by a white cell surface). (E) At later time points (1–2 days), parasites begin to transition out of neutrophils into macrophage/monocytes and DCs. Parasite acquisition by these phagocytes can occur via uptake of released, viable organisms from infected neutrophils, or via uptake of parasitized neutrophils, i.e. the ‘Trojan Horse’ route. Infected macrophage/monocyte and DC populations are also exposed to apoptotic bodies and large numbers of uninfected, apoptotic neutrophils that will down-modulate both innate mechanisms of parasite killing and APC functions. (F) During the ‘silent’ phase of parasite growth, neutrophils are persistently recruited to and maintained in the bite site by sand fly derived factors, and parasite killing and APC functions will continue to be suppressed, associated with production of non-inflammatory cytokines PGE₂ and TGF-β. (G) Parasites propagate in inflammatory, monocyte –derived cells in the skin, and increase to sufficient numbers so that they are eventually taken up by immunocompetent DCs in the skin or draining lymph node, initiating T cell priming and the healing phase of disease.